Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])CC=C[CH2:2]1.C[N+]1([O-])CC[O:20]CC1.[CH3:24][C:25]([CH3:27])=[O:26]>O.O=[Os](=O)(=O)=O>[OH:26][C@H:25]1[C@@H:27]([OH:20])[CH2:2][N:1]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:24]1
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1C[C@@H](O)[C@@H](O)C1
Reaction time: 19 h
Yield: 15 %

Procedure:
Phenylmethyl 2,5-dihydro-1H-pyrrole-1-carboxylate (commercially-available) (5.07 g, 25 mmol) was dissolved in a mixture of acetone (25 mL) and water (10 mL). NMO (5.9 g, 50 mmol) was added followed by catalytic OsO4. The reaction was stirred for 19 hours and then quenched by the addition of an aqueous solution of Na2S2O3. A standard work-up followed by silica gel chromatography (3:1 Hexane:ethyl acetate to pure ethyl acetate to 9:1 DCM: MeOH) yielded phenylmethyl (cis)-3,4-dihydroxy-1-pyrrolidinecarboxylate (0.872 g, 15%) as a clear oil. LCMS: (M+H)+: 237.9.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[N:13](C(OC(C)(C)C)=O)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([OH:21])=[CH:16][CH:15]=3)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.Cl[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-:40].[Cs+].[Cs+]>CN(C)C=O.O.C(O)(=O)C>[N:33]1([CH2:32][CH2:31][O:21][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]([C:11]2[C:2](=[O:40])[NH:3][C:4]4[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:20]3)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: ClCCN1CCCCC1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(O)ccc21
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2ccccc2cc1-c1cc2cc(OCCN3CCCCC3)ccc2[nH]1
Temperature: 50 °C

Procedure:
A mixture of tert-butyl 2-(2-chloro-3-quinolinyl)-5-hydroxy-1H-indole-1-carboxylate 1-8 (395 mg, 1.00 mmol, 1 equiv), 1-(2-chloroethyl)-piperidine hydrochloride (276 mg, 1.50 mmol, 1.50 equiv), and cesium carbonate (978 mg, 3.00 mmol, 3.00 equiv) in N,N-dimethylformamide (5 mL) was heated at 50° C. for 2 h. The reaction mixture was concentrated, and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water then brine, dried over magnesium sulfate, and concentrated to give a pale-yellow foam. The foam was dissolved in a 1:1 mixture of water and acetic acid (60 mL), and the resulting solution was heated at 110° C. for 12 h. The reaction mixture was concentrated, and the residue was stirred in aqueous saturated sodium bicarbonate solution which yielded a tan solid. The tan solid was filtered, then suspended in warm ethanol (2×20 mL) and filtered to give 3-[5-(2-piperidin-1-yl-ethoxy)-1H-indol-2-yl]-1H-quinolin-2-one (1-9) as a yellow solid. The ethanolic filtrate was concentrated and the residue purified by flash column chromatography (5% ethanol saturated with ammonia in ethyl acetate to afford additional 1-9. 1H NMR (400 MHz, (CD3)2SO) δ12.14 (s, 1H), 11.41 (s, 1H), 8.50 (s, 1H), 7.73 (br d, 1H, J=7.9 Hz), 7.51 (br t, 1H, J=7.6 Hz), 7.41 (d, 1H, J=8.6 Hz), 7.37 (br d, 1H, J=8.2 Hz), 7.24 (br t, 1H, J=7.7 Hz), 7.21 (br s, 1H), 7.06 (br s, 1H), 6.76 (dd, 1H, J=8.6,2.2 Hz), 4.06 (t, 2H, J=5.9 Hz), 2.67 (t, 3H, J=5.5 Hz), 2.45 (br m, 4H), 1.51 (br m, 4H), 1.39 (br m, 2H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.O[CH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:47](=[O:48])[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:49])[CH2:35][CH2:34]1.[CH3:50][C:51]([SH:53])=[O:52]>C1COCC1.O.CC(=O)OCC>[C:51](=[O:52])([S:53][CH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:47](=[O:48])[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:49])[CH2:35][CH2:34]1)[CH3:50]
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Reactant: CC(=O)S
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)SC1CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of PPh3 (1.28 g, 4.9 mmol) in THF (12 mL) was added dropwise DEAD (852 mg, 4.9 mmol) at −10° C. After the white solid was appeared, compound 2-(4-hydroxycyclohexyl)isoindoline-1,3-dione (600 mg, 2.45 mmol) was added, followed by CH3COSH (0.35 mL, 4.9 mmol) at −10° C. The mixture was stirred at room temperature overnight. TLC (PE:EA=1:1) showed the reaction was complete. The mixture was poured into water (200 mL) and extracted with EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL×3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo to give S-(4-(1,3-dioxoisoindolin-2-yl)cyclohexyl) ethanethioate (600 mg, 81%) as a white solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Cl[C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>C(O)CC>[CH2:1]([NH:4][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:15][CH2:16][CH2:17][N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:23]1)[CH2:2][CH3:3]
Reactant: CCCN
Reactant: Clc1ncnc2c1ncn2CCCN1CCN(c2ccccc2)CC1
Solvent: CCCO
Product: CCCNc1ncnc2c1ncn2CCCN1CCN(c2ccccc2)CC1
Reaction time: 15 h
Yield: 65 %

Procedure:
50 ml of n-propylamine are added to a solution of 10.7 g (0.03 mole) of 6-chloro-9-[3-(4-phenyl-piperazino)-propyl]-purine (produced as hereinabove described) in 100 ml of n-propanol, whereafter the reaction mixture is heated under reflux for 5 hours. After standing for 15 hours at ambient temperature, the reaction mixture is evaporated in a vacuum and the residue extracted with ether. After evaporation of the solvent, there are obtained 9.0 g (79% of theory) of crude product, which has a melting point of 64°-66° C. After recrystallization from ether, there are obtained 7.4 g (65% of theory) of N6 -n-propyl-9-[3-(4-phenyl-piperazino)-propyl]-adenine, which has a melting point of 67°-68° C.
Reaction SMILES: [N:1]1C=CC=CC=1.Br[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[NH2:16][C:17]1[C:22]([CH:23]=O)=[CH:21][N:20]=[C:19]([Br:25])[CH:18]=1.N1CCCC1>CCO>[NH2:1][C:8]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][N:20]=[C:19]([Br:25])[CH:18]=2
Reactant: CCOC(=O)C(=O)CBr
Reactant: c1ccncc1
Reactant: Nc1cc(Br)ncc1C=O
Solvent: C1CCNC1
Solvent: CCO
Product: CCOC(=O)c1nc2cc(Br)ncc2cc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of pyridine (0.11 mL, 1.4 mmol) and ethyl bromopyruvate (0.19 mL, 1.5 mmol) in EtOH (2.2 mL) was stirred at 70° C. in a sealed vial for 16 h. The reaction mixture was allowed to cool to ambient temperature prior and a solution of 4-amino-6-bromonicotinaldehyde (0.278 g, 1.38 mmol) and pyridine (0.67 mL, 8.3 mmol) in EtOH (1 mL) was then added. The resulting mixture was heated at 100° C. in a sealed vial for 16 h. Stirring was continued at 100° C. for an additional 24 h. Pyrrolidine (0.23 mL, 2.8 mmol) was added and stirring was continued at 100° C. for 5 h in a sealed vial. The crude reaction mixture was purified by flash chromatography (40 g silica gel column, eluting with 0-100% EtOAc/hexanes) to give the sub-title compound. LCMS (ESI) calc. for C11H11BrN3O2 [M+H]+: m/z=296.0. found: 295.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>C(OCCO)C>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:23]2[C:32]3[C:27](=[CH:28][N:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)=[CH:8][CH:7]=1
Reactant: Clc1nccc2cnccc12
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCCO
Product: COC(=O)[C@H](Cc1ccc(Nc2nccc3cnccc23)cc1)NC(=O)OC(C)(C)C
Yield: 46.7 %

Procedure:
(S)-3-(4-Amino-phenyl)-2-tert-butoxycarbonylamino propionic acid methyl ester (574 mg, 1.95 mmol), 1-Chloro-2,6-naphthyridine (350 mg, 2.13 mmol) (prepared according to the method of Van der Plas, H. C. et al J. Heterocyclic Chem. 1981, 18, 1349) and DIPEA (372 μl, 2.13 mmol) in 2-ethoxyethanol (0.5 ml) were stirred at 130° C. under N2 overnight. The reaction mixture was partitioned between EtOAc (70 ml) and saturated aqueous NaHCO3 (30 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3×30 ml). The combined organic extracts were dried (MgSO4) and the solvents eliminated in vacuo. The residue was purified by flash chromatography (5:1 to 1:1 hexanes/EtOAc) to give (S)-2-tert-butoxycarbonylamino-3-[4-([2,6]naphthyridin-1-ylamino)phenyl] propionic acid methyl ester (385 mg, 47%) as an orange foam.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[N:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[N:11][N:12]=2)=[CH:4][CH:3]=1.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:19]1([NH:22][C:23]([C:24]2[CH:29]=[C:28]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:9][C:10]([C:13]5[N:14]([CH3:18])[CH:15]=[CH:16][CH:17]=5)=[N:11][N:12]=4)=[CH:4][CH:3]=3)[C:27]([CH3:30])=[CH:26][CH:25]=2)=[O:40])[CH2:20][CH2:21]1
Reactant: Cn1cccc1-c1nnc(-c2ccc(I)cc2)o1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(-c3cccn3C)o2)cc1
Temperature: 80 °C

Procedure:
2-(4-Iodophenyl)-5-(1-methyl-1H-pyrrol-2-yl)-1,3,4-oxadiazole (intermediate 38) (35 mg), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (33 mg), tetrakis(triphenylphosphine)palladium (13 mg) and aqueous sodium carbonate (1M, 0.11 ml) in DME (3 ml) were mixed and heated at 80° C. for 18 hours. The reaction was purified by bond-elut (silica), eluting with an ethyl acetate/cyclohexane gradient to give, after evaporation of the solvent, N-cyclopropyl-6-methyl-4′-[5-(1-methyl-1H-pyrrol-2-yl)-1,3,4-oxadiazol-2-yl]-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Br:24])[C:18]([OH:20])=[O:19])[CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC#N>[CH2:31]([O:19][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:23]([Br:24])=[C:15]([CH2:14][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH3:13])[CH:16]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrCc1ccccc1
Reactant: CCN(Cc1cc(C(=O)O)ccc1Br)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN(Cc1cc(C(=O)OCc2ccccc2)ccc1Br)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-[(N-benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-bromo-benzoic acid (8.9 g, 22.6 mmol) in MeCN (400 mL) was added cesium carbonate (18.4 g, 56.5 mmol), followed by benzyl bromide (2.95 mL, 24.9 mmol), and the reaction was stirred at room temperature overnight. The mixture was filtered and extracted with EtOAc and washed with H2O. The organic layer was dried and concentrated, and the residue was purified by silica gel chromatography (0-25% EtOAc in hexanes) to give 3-[(N-benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-bromo-benzoic acid benzyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.P(Cl)(Cl)(Cl)=O.C[O:12][CH:13](OC)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[OH-].[Na+].CNC>O.C(Cl)(Cl)Cl>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:14](=[CH:3][N:2]([CH3:5])[CH3:1])[CH:13]=[O:12])=[CH:17][CH:18]=1
Reactant: COC(COc1ccc(Cl)cc1)OC
Reactant: CN(C)C=O
Agent: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN(C)C=C(C=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Dimethylformamide (109.5 g., 1.5 moles) was cooled in an ice-water bath. Phosphorus oxychloride (229.5 g., 1.5 moles) was added dropwise over 1.5 hours and the reaction mixture then allowed to stir for 45 minutes at room temperature. Chloroform (300 ml.) was added and then 4-chlorophenoxyacetaldehyde dimethylacetal (122 g., 0.5 moles) and the mixture refluxed for approximately 16 hours. The reaction was cooled to room temperature and added slowly to approximately 300 ml. of chloroform mixed with ice and water while maintaining the pH approximately 10 with sodium hydroxide. Aqueous 40% dimethylamine (400 ml.) was added, the organic layer separated and the aqueous extracted with additional chloroform. The chloroform extracts were combined, dried over anhydrous sodium sulfate, concentrated to a semisolid, and crystalline product recovered by trituration with isopropyl ether (95 g., Rf 0.25 on thin layer chromatography on silica gel with ethyl acetate as eluant).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([Br:19])=[N:17][CH:18]=2)[CH2:9]1.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH:10]2[CH2:11][N:8]([CH3:2])[CH2:9]2)=[CH:18][N:17]=1
Reactant: Brc1ccc(OC2CNC2)cn1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CC(Oc2ccc(Br)nc2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 104.2 %

Procedure:
In a solution of 5-(Azetidin-3-yloxy)-2-bromo-pyridine trifluoro-acetic acid salt (0.5 g, 1.46 mmol) in dichloromethane (20 mL), add formaldehyde aqueous solution (37%, 0.58 mL, 7.29 mmol). Then add Na(OAc)3BH (0.774 g, 3.65 mmo) carefully. The reaction was stirred at room temperature under argon for 45 min. The reaction was quenched with water (30 mL), and then extracted with dichloromethane (3×20 mL). The combined organic phase was washed thoroughly with brine and water. Evaporation of solvent afford 2-Bromo-5-(1-methyl-azetidin-3-yloxy)-pyridine (0.37 g, yield 98%), which was pure enough for next step.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33](Cl)[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]>>[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([NH:9][CH2:8][CH2:7][CH2:6][N:1]5[CH:5]=[CH:4][N:3]=[CH:2]5)[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: NCCCn1ccnc1
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(NCCCn5ccnc5)n4)cc3)cc12

Procedure:
Using 3-imidazol-1-yl-propylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:10]([CH2:16][N:17]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:43][S:44](Cl)(=[O:46])=[O:45].Cl>CCOC(C)=O>[CH3:43][S:44]([O:15][CH2:14][C:12]1[CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]=[C:10]([CH2:16][N:17]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:11]=1)(=[O:46])=[O:45]
Reactant: Cc1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(CO)cc(-c3ccc(F)cc3)c2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N(Cc2ccc(F)cc2)Cc2cc(COS(C)(=O)=O)cc(-c3ccc(F)cc3)c2)cc1
Reaction time: 1 h

Procedure:
To a solution of N-((4′-fluoro-5-(hydroxymethyl)biphenyl-3-yl)methyl)-N-(4-fluorobenzyl)-4-methylbenzenesulfonamide (100 mg, 0.203 mmol) and Et3N (0.15 mL) in EtOAc (5 mL) at −30° C. was added methanesulfonyl chloride (25 mg, 0.218 mmol) in EtOAc (10 mL) slowly with stirring. After 1 h, a small amount of 1N aq HCl and EtOAc were added to the reaction mixture. The EtOAc layer was separated, dried over MgSO4 and concentrated in vacuo to obtain the product as a viscous material. It was enough pure to use for next step without any further purification. MS (ESI): (M+H)+=572.18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:9]1[O:10][C:11]3([CH2:17][S:18][C:8]=1[C:7](=[O:22])[C:6]2=[O:23])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3.[F:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C@@H:31]2[CH2:33][O:32]2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C@@H:31]([OH:32])[CH2:33][N:14]2[CH2:15][CH2:16][C:11]3([O:10][C:9]4[C:19]5[C:5]([C:6](=[O:23])[C:7](=[O:22])[C:8]=4[S:18][CH2:17]3)=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=5)[CH2:12][CH2:13]2)=[CH:27][CH:26]=1
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Reactant: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCNCC2)CS1
Product: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCN(C[C@H](O)COc3ccc(F)cc3)CC2)CS1

Procedure:
Compound 206 was synthesized using 8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-fluorophenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=189-191° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.73 (d, J=8.6 Hz, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 7.31 (dd, J=1.5, 6.8 Hz, 3H), 6.98 (d, J=3.5 Hz, 1H), 4.90 (d, J=4.7 Hz, 1H), 4.05-3.92 (m, 2H), 3.87 (s, 3H), 3.06 (s, 2H), 2.87-2.72 (m, 2H), 2.57-2.32 (m, 4H), 2.01-1.90 (m, 2H), 1.86-1.73 (m, 2H). LCMS: 500 [M+H].
Reaction SMILES: [CH3:1][N:2]([CH2:6][C:7]#[CH:8])[C:3](=[O:5])[CH3:4].[CH2:9]=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>O1CCOCC1>[CH3:1][N:2]([CH2:6][C:7]#[C:8][CH2:9][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:3](=[O:5])[CH3:4]
Reactant: C=O
Reactant: C#CCN(C)C(C)=O
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: CC(=O)N(C)CC#CCN1CCCC1
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, a solution containing 13.0 g. (0.12 mole) of N-methyl-N-propargylacetamide, 5.8 g. of paraformaldehyde, 10.5 g. (0.15 mole) of pyrrolidine and a trace of cuprous chloride in 80 ml. of dioxane was refluxed for 5 hrs. and allowed to stand overnight. The mixture was filtered remaining oil was distilled and redistilled giving N-methyl-N-(4-pyrrolidino-2-butynyl)acetamide, boiling at 120° C. at 0.03 mm.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)[CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.CCOC(C)=O.O>[N:19]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[CH:12]3)[CH:3]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1cc(Oc2ccc3ncccc3c2)ncn1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1cc(Oc2ccc3ncccc3c2)ncn1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 9.4 g (36.4 mMol) of 6-chloro-4-(quinolin-6-yloxy)-pyrimidine in 110 ml DMF, 4.74 g (73 mMol) NaN3 are added. After stirring for 60 min at 60° C., the solution is diluted with EtOAc and water. The aqueous layer is separated off and extracted 2× with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrate in vacuo to give the crude title compound which is used as such in the next step: MS: [M+1]+=265.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[C:10]1=[O:22].[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:35].C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([CH:14]4[CH2:15][CH2:16][C:17]([F:20])([F:21])[CH2:18][CH2:19]4)[C:10]3=[O:22])=[C:6]([Cl:23])[CH:5]=2)=[CH:38][CH:37]=1)=[O:35]
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCC(F)(F)CC1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCC(F)(F)CC4)C3=O)c(Cl)c2)cc1
Reaction time: 8 h
Yield: 57.6 %

Procedure:
Treat a solution of Trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-1-(4,4-difluoro-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenyl ester (1.8 g, 3.5 mmol), 4-Methoxycarbonylphenylboronic acid (1.3 g, 7.0 mmol), and Tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.4 mmol) in DME (20 mL) with 2M aqueous K2CO3 (5.2 mL). Heat the reaction to 80° C. and stir overnight. Cool the reaction and quench with 1N HCl. Extract the aqueous with EtOAc. Wash the organic with brine, dried over MgSO4, and filter. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute the pure product. Remove the solvent to afford 1.0 g (57%) of desired product. MS (m/e): 498 (M+1).
Reaction SMILES: [C@@H:1]1([O:11][CH2:12][CH2:13][NH:14][C:15](=[O:32])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C@@H:27]([C:29]([OH:31])=[O:30])[NH2:28])=[O:21])[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].O=C1CCC(=O)N1[O:40][C:41](=O)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:51]([O:50][C:48](=[O:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][C:41]([NH:28][C@H:27]([C:29]([OH:31])=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:15]([NH:14][CH2:13][CH2:12][O:11][C@@H:1]1[O:9][C@@H:8]([CH3:10])[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]1[OH:3])=[O:32])=[O:40])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](N)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: O=C(CCCCCCC(=O)ON1C(=O)CCC1=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1O[C@@H](OCCNC(=O)CCCCC(=O)NCCCC[C@H](NC(=O)CCCCCCC(=O)OCc2ccccc2)C(=O)O)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N6-[6-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)-6-oxohexanoyl]-L-lysine (310 mg, 0.669 mmol) in DMF (20 mL) at 0° C. was added benzyl 8-[(2,5-dioxopyrrolidin-1-yl)oxy]-8-oxooctanoate (242 mg, 0.669 mmol), followed by the addition of DIPEA (0.117 ml, 0.669 mmol). The reaction was warmed to 25° C. and stirred at this temp for 18 hr. The reaction mixture was concentrated, and the residue was purified by flash chromatography on C18 reverse phase silica gel, eluting with 0-30% CAN in water, to give the title compound. UPLC Method B: m/e=710.423 [M+1]; Rt=4.59 min.